The present Invention relates to novel pharmaceutical compositions combining the agents lamivudine and zidovudine into a single dosage form, useful in the treatment of diseases in mammals, including humans. The present Invention is particularly useful for treating viral infections, particularly retroviral infections, including human immunodeficiency virus (HIV).
HIV causes a variety of clinical conditions including acquired immune deficiency syndrome (AIDS) and chronic neurological disorders. The recent advent of a variety of multiple-drug treatment regimens has dramatically improved the treatment of HIV infected patients. Prior to these multiple-drug regimens, treatment was often limited to single drugs with limited effectiveness.
Single drug treatment regimens typically require long term treatment increasing the incidence of unwanted side effects. Moreover, single drug therapies are particularly vulnerable to mutations in the HIV virus, leading to drug resistant variants of HIV.
The use of multiple drug therapies may reduce the development of drug-resistant strains of HIV because one drug will usually cancel out mutations against other drugs. Multiple-drug therapies may even inhibit replication of HIV viruses for a period of time sufficient to eliminate HIV from the body.
The success of modern multiple-drug treatments for HIV often requires strict compliance with a complex treatment regimen that can require the administration of many different drugs per day, administered at precisely timed intervals with careful attention to diet. Patient non-compliance is a well known problem accompanying such complex treatment regimens. See Goodman & Gilman, The Pharmacological Basis of Therapeutics, 9th ed., pp. 1704-1705 (1996), incorporated herein by reference. Patient non-compliance is an important problem in the treatment of HIV because such noncompliance may lead to the emergence of multiple-drug resistant strains of HIV.
Two of the many compounds which are commonly included in multiple-drug treatment regimens for HIV are zidovudine and lamivudine. Lamivudine (also known as 3TC.TM..sup.1) is a synthetic nucleoside analogue, chemically known as (2R,cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2- one. Lamivudine has also been referred to as (-)2',3'-dideoxy, 3'thyacytidine. Lamivudine has proven antiviral activity against human immunodeficiency virus (HIV) and other viruses such as hepatitis B. Lamivudine is commercially available from Glaxo Wellcome Inc. under the tradename EPIVIR.TM..sup.2. FNT .sup.1 3TC is a trademark of the Glaxo Wellcome group of companies. Registered in the United States Patent and Trademark office. FNT .sup.2 EPIVIR is a trademark of the Glaxo Wellcome group of companies. Registered in the United States Patent and Trademark office.
Zidovudine, chemically known as 3'-azido-3'-deoxythymidine, is a pyrimidine nucleoside analogue commercially available from Glaxo Wellcome Inc. under the tradename RETROVIR.TM..sup.3 for the treatment of HIV and other viruses. Zidovudine is further described in U.S. Pat. Nos. 4,818,538, 4,828,838, 4,724,232, 4,833,130 and 4,837,208, all of which are incorporated herein by reference. FNT .sup.3 RETROVIR is a trademark of the Glaxo Wellcome group of companies. Registered in the United States Patent and Trademark office.
In November of 1995, the FDA granted accelerated approval for the use of lamivudine in combination with zidovudine for first-line treatment of HIV-infection in adults and children. It is now known that lamivudine exhibits unexpected advantages when used in combination with known inhibitors of HIV replication. In particular, lamivudine shows a synergistic antiviral effect and/or reduction in cytotoxicity when used in combination with zidovudine. In controlled clinical trials, combination therapy with lamivudine and zidovudine delayed the emergence of zidovudine-resistant mutations of HIV.
Segregation of active ingredients in pharmaceutical powders and granulations is a widely recognized problem that can result in inconsistent dispersions of the active ingredients in final dosage forms. Some of the main factors contributing to segregation are particle size, shape and density. Segregation is particularly troublesome when attempting to formulate a single homogenous tablet containing multiple active ingredients having different densities and different particle sizes. Previous attempts to formulate tablets containing lamivudine and zidovudine were hindered by precisely such segregation problems. Although mixed blends were initially homogeneous, the active ingredients segregated during material handling and prior to tablet compression.
Glidants are substances that have traditionally been used to improve the flow characteristics of granulations and powders by reducing interparticulate friction. See Lieberman, Lachman, & Schwartz, Pharmaceutical Dosage Forms: Tablets, Volume 1, p. 177-178 (1989), incorporated herein by reference. Glidants are typically added to pharmaceutical compositions immediately prior to tablet compression to facilitate the flow of granular material into the die cavities of tablet presses. Glidants include: colloidal silicon dioxide, asbestos free talc, sodium aluminosilicate, calcium silicate, powdered cellulose, microcrystalline cellulose, corn starch, sodium benzoate, calcium carbonate, magnesium carbonate, metallic stearates, calcium stearate, magnesium stearate, zinc stearate, stearowet C, starch, starch 1500, magnesium lauryl sulfate, and magnesium oxide.
Research into the problem of segregation in pharmaceutical compositions has surprisingly demonstrated that glidants can be used to increase and aid blend composition homogeneity. The novel compositions of the present Invention use glidants to effect and maintain homogeneity of active ingredients during handling prior to tablet compression.
It is therefore an object of the present Invention to provide a pharmaceutical formulation combining the active ingredients lamivudine and zidovudine, or pharmaceutically acceptable derivatives thereof, in a sufficiently homogenized form, and a method for using this pharmaceutical formulation.
A further object of the present Invention is to utilize glidants to reduce the segregation of active ingredients in pharmaceutical compositions during pre-compression material handling.
A still further object of the present Invention is to provide a pharmaceutical formulation combining the active ingredients lamivudine and zidovudine, or pharmaceutically acceptable derivatives thereof, with a pharmaceutically acceptable glidant, resulting in a mixture characterized by a pharmaceutically acceptable measure of homogeneity.
Another object of the present Invention is to provide a pharmaceutical formulation comprising zidovudine, or a pharmaceutically acceptable derivative thereof, and lamivudine, or a pharmaceutically acceptable derivative thereof, together with one or more pharmaceutically acceptable carriers and optionally, other therapeutic and/or prophylactic ingredients. The carrier(s) must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
Still another object of the present Invention is to simplify treatment regimens for HIV and other viruses with the goal of enhancing patient compliance by providing a simplified dosage form containing pharmaceutically acceptable amounts of lamivudine and zidovudine or pharmaceutically acceptable derivatives thereof. These objects and further objects will become evident from the description of the invention below.